Calcium in intracellular stores can control plasma membrane calcium permeability by an unknown mechanism. The imidazole anti-fungal agent, econazole has been proposed to inhibit store-regulated calcium influx in platelets by blocking the signal between empty internal calcium stores and the plasma membrane. We have previously suggested that such a signal may be related to calcium dependent tyrosine phosphorylation. To study the correlation between store-regulated calcium influx and tyrosine phosphorylation we utilized thapsigargin to deplete calcium stores and observed the effects of econazole and elevation of CAMP, an inhibitor of platelet tyrosine phosphorylation. Both econazole and CAMP inhibited thapsigargin-induced tyrosine phosphorylation and thapsigargin-induced calcium influx as measured by 45Ca2+. Only CAMP decreased thapsigargin- induced efflux from 45Ca2+ loaded platelets while neither econazole or CAMP elevation affected calcium efflux from resting platelets. When calcium stores were depleted with thapsigargin prior to addition of inhibitors so that the store signal to the plasma membrane was already generated only econazole continued to inhibit influx of calcium. These observations indicate that CAMP inhibits generation of the thapsigargin-induced store signal while econazole acts as a calcium channel blocker.